Toxoplasma gondii (T.gondii) is the etiologic agent of toxoplasmosis, a prevalent parasitosis infecting one-third of the human population worldwide. Under the host immune control, tachyzoites responsible for acute toxoplasmosis (AT), transform into latent bradyzoites responsible for chronic toxoplasmosis (CT). In immunocompromised patients, CT may reactivate leading to a potentially life-threatening condition. Several associations between CT and behavioral neurological complications were highlighted. Yet, a direct pre-clinical or clinical implication of toxoplasmosis with most of these diseases remains elusive. Moreover, an approved and efficient treatment targeting CT is still lacking despite its high prevalence. We previously demonstrated the high potency of an immunomodulatory drug, Imiquimod, against AT and CT, and unraveled its molecular mechanism of action. Briefly, Imiquimod induces interconversion from bradyzoites to tachyzoites, upregulated Toll-like receptors, leading to the consequent activation of the MyD88 pathway, triggering the host immune response and the control of reactivated Toxoplasma foci. Here, we investigated the effects of Imiquimod or the first-line therapy (Sulfadiazine (S) and Pyrimethamine (P)) followed by Imiquimod on CT-associated behavioral complications, namely anxiety-like behavior and hippocampal cognitive functions, in a CT rat model. Consistent with our previous results in mouse models, Imiquimod decreased the number of cysts in the brain of chronically infected rats and induced the reactivation of bradyzoites into tachyzoites. Strikingly a higher potency was observed when chronically infected rats were treated with Imiquimod followed by the combination S+P. Moreover, an upregulation of proinflammatory cytokines in the brains of chronically infected rats was observed upon treatment with Imiquimod alone or followed by S+P. This upregulation triggered a concurrent anti-inflammatory immune response to lessen the proinflammatory immune-pathological response. Importantly, in chronically infected rats with T. gondii, Imiquimod and more potently Imiquimod followed by S+P alleviated the anxiety-like behavior and reversed Toxoplasma-induced the learning deficits observed in untreated infected rats. Collectively, our results enhance our knowledge on the implications of toxoplasmosis on behavioral aberrancies, and open perspectives towards new therapeutic approaches targeting CT and its associated diseases